SUMMARY The overall goal of this project is to understand the mechanisms by which general anesthetics suppress consciousness and allow its return during emergence. Our general hypothesis is that anesthetics remove consciousness by disrupting functional integration across cortical neuronal networks. The proposed project builds upon our one-and-a-half decade-long investigation into the systems neuroscience mechanisms of anesthesia. In our prior work, we investigated the effect of volatile anesthetics on the power and coherence of gamma oscillations, and on their preferential role in corticocortical feedback vs. feedforward signaling as a neuronal correlate of unconsciousness. Subsequently, we focused on how the dynamics of spiking activity of cortical neurons and the complexity of their interactions were modulated by anesthetics. Here, using optogenetic and electrical microstimulation techniques, we extend this work to examine how cortical top- down, subcortical bottom-up and local state modulations alter cortical neuronal interactions associated with loss and return of consciousness. We will examine spontaneous ongoing activity and sensory stimulus-related neuronal interactions across visual and association cortex and will directly interrogate functional circuits using selective microstimulation for the first time. We will test the hypothesis that the complexity of spontaneous and stimulus-driven neuronal interactions will undergo a distinct transition associated with loss and recovery of consciousness as a function brain state modified by anesthetic dose, top-down and bottom-up modulation, and general cortical excitability. We will study the concentration-dependent effect of four representative anesthetic agents with different pharmacological profiles: desflurane, propofol, dexmedetomidine, and ketamine to find a common, agent-invariant neuronal correlate of unconsciousness. State changes at select anesthetic concentrations will be elicited by cortical or subcortical stimulation, neuronal silencing, and subnoxious somatosensory arousal. Parallel spike trains and local field potentials will be recorded from visual and adjacent association cortices using chronically implanted multielectrode arrays in unrestrained rats. Spontaneous and visual stimulus-related excitatory and inhibitory monosynaptic connectivity, neuronal interaction complexity, and microstimulation-induced effective connectivity within and between each cortical region will be derived. These experiments will provide essential new information about the role of cortical neuronal interactions in information integration as a function of conscious state and help uncover the degree to which both globally and locally driven neuronal activity is altered by brain states. The proposed work will advance our understanding of the neural mechanism of anesthesia and the neurobiological basis of consciousness at an integrative level. Our findings will augment the basic scientific knowledge necessary for the future development of novel electrophysiological monitoring of the state of consciousness and for the development of new approaches to manipulate the state consciousness for general anesthesia.